Approximately 4 million people in the United States and 20 million people worldwide suffer from Alzheimer's disease (AD), a neurodegenerative disorder leading to dementia that presently has no therapeutic cure. Deregulation of cyclin-dependent kinase 5 (Cdk5) by p25 has been shown to play a role in the pathogenesis of AD. AD pathology is also strongly linked to the intracellular mislocalization of APP. However, the relationship between APP phosphorylation by Cdk5 and APP localization has yet to be investigated. This application tests the hypothesis that APP phosphorylation by Cdk5 is linked to APP localization and that mislocalization or deregulation of Cdk5 leads to aberrant APP phosphorylation and trafficking. The proposed experiments center on the mechanisms and factors regulating APP metabolism and seek to further understand the function of APP and Cdk5 by investigating (a) the temporal and spatial localization of APP phosphorylation by Cdk5, (b) the function of Cdk5-mediated APP phosphorylation through the identification proteins that interact with phosphorylated APP, and (c) the role of APP phosphorylation by Cdk5 in vivo by utilizing transgenic and knockout mice. Completion of these studies will provide insight into the molecular mechanisms by which Cdk5 may contribute to the formation of amyloid plaques. Finding such connections would begin to link the mechanism of formation of plaques and neurofibrillary tangles, the two major causes of cell death in AD. In addition, the results may provide general mechanisms responsible not only for the etiology of AD but for other neurodegenerative disorders, as well. Finally, the proposed work may aid in developing benign and effective pharmacological agents as potential drug therapies for AD by specifically blocking the formation or activity of p25/Cdk5.